Hepatitis A virus (HAV) is a picornavirus that causes acute hepatitis in humans. Our lab identified HAVcr-1, a gene coding for a surface glycoprotein on the GL37 clone of African green monkey kidney (AGMK) cells, as a receptor for HAV (Kaplan et al., EMBO J. 15:4282-4269, 1996). Molecular cloning and sequence analysis of the HAVcr-1 cDNA revealed that it codes for a class I, integral membrane glycoprotein termed havcr-1. The extracellular domain of havcr-1 contains an N-terminal cys-rich region followed by a mucin-like region. We recently showed that dog cells transfected with the HAVcr-1 cDNA bound HAV and protective monoclonal antibody (MAb) 190/4. However, dog cells expressing an havcr-1 construct containing a deletion of the cys-rich region did not bind HAV and MAb 190/4. These data indicated that the cys-rich region of havcr-1 is required for binding of HAV and MAb 190/4 (Thompson et al., J. Virol. 72:3751-3761, 1998). Although MAb 190/4 protected AGMK clone GL37 cells against HAV infection, it did not react with havcr-1 expressed at the cell surface of BS-C-1 and CV-1 cells, two widely used AGMK cell lines. Nucleotide sequence analysis of the BS-C-1 and CV-1 HAVcr-1 cDNAs revealed that they encoded 99% identical havcr-1 glycoproteins that shared 92% identity with the GL37 havcr-1. Studies with chimeras of GL37 havcr-1 and BS-C-1 havcr-1 showed that the K108Q substitution in the BS-C-1 havcr-1, which was responsible for the lack of reaction with MAb 190/4, did not affect HAV-receptor function (Feigelstock et al., J. Virol. 72:6218-6222, 1998). To determine the existence of a human homolog of HAVcr-1 (huHAVcr-1), we amplified by reverse transcription-PCR a huHAVcr-1 cDNA from human liver and kidney mRNA. Nucleotide sequence analysis revealed that the huHAVcr-1 cDNA encoded a 359-amino acid huhavcr-1 which was 79% identical to the simian havcr-1. Northern blot analysis revealed that the huHAVcr-1 mRNA is expressed in liver, small intestine, colon, spleen, and other organs, and overexpressed in kidney and testis. Dog cell trasnfectants expressing huhavcr-1 bound HAV and gain a limited level of susceptibility to HAV infection. Our data showed that huhavcr-1 is a binding receptor for HAV and suggested that it also is a functional receptor for HAV (Thompson et al., J. Virol. 72:6621-6628, 1998).